Prostaglandins are synthesized in mammals, including humans and are involved in inflammatory disease. Prostaglandins induce/contribute to a myriad of conditions, including the changes in vascular permeability leading to tissue edema and swelling, biochemical changes in the production of extracellular matrix degrading enzymes, such as fibroblast collagenase and elastase, fever and pain. Prostaglandins alter the contractile properties of vascular and non-vascular smooth muscle, leading to vasodilatation, vasoconstriction, uterine contractions, and bronchospasm.
The release of arachidonic acid from cellular membrane phospholipids and the subsequent production of eicosanoids such as cyclooxygenase products and lipoxygenase products is a hallmark feature of nearly all inflammatory diseases. Free arachidonic acid is the obligate precursor of cyclooxygenase, and its products. Under unstimulated cellular conditions, nearly all arachidonic acid is esterified in membrane phospholipids and is unavailable for eicosanoid biosynthesis. However, when a cell encounters certain extracellular stimuli, phospholipase A.sub.2 cleaves arachidonic acid from the phospholipid, thereby permitting the arachidonic acid to be converted into prostaglandins by cyclooxygenase.
Once liberated, the bifunctional enzyme, cyclooxygenase, catalyzes the formation of prostaglandin (hereinafter "PGG.sub.2 ") by a bis-cyclooxygenation reaction. PGG.sub.2 then undergoes a peroxidation reaction to form prostaglandin H.sub.2 (hereinafter "PGH.sub.2 ") which is the immediate precursor for all subsequent prostaglandin synthetic reactions. In certain cell types, primarily platelets in which thromboxane (TxA.sub.2) is the major arachidonic acid metabolite, thromboxane synthase converts PGH.sub.2 into thromboxane. Thromboxane is a potent vasoconstrictor and involved in vasoconstriction, coagulation, and preeclampsia. Other cell types, such as endothelial cells, synthesize mainly prostacyclin (PGI.sub.2) which is produced from PGH.sub.2 via prostacyclin synthase. ##STR1## Prostaglandin E.sub.2 and prostaglandin F.sub.2.alpha., hereinafter "PGE.sub.2 " and "PGF.sub.2.alpha. " are the stimulators of uterine contractions and cervical dilatation and effacement which culminate in labor and delivery of the fetus at term. Keirse, M. J. N. C. "Eicosanoids in Human Pregnancy and Parturition", Eicosanoids in Reproduction, Mitchell, M. D., ed. 1990; CRC Press, Boca Raton, pp. 199-222.
The levels of PGE.sub.2 and PGF.sub.2.alpha. and their metabolites are also increased in the amniotic fluid of women in preterm labor with clinical signs of infection and are believed to be a causative factor of pre-term labor, Romero, R., Avila, C., and Sepulveda, W. "The Role of Systemic and Intrauterine Infection in Preterm Labor In: Preterm Birth: Causes, Prevention, and Management," 2d. ed., Fuchs, A. -R., Fuchs, F., and Stubblefield, P. G., eds., MacGraw-Hill, Inc., New York, 97-136. Preterm labor occurs in approximately 8-9% of all pregnancies, but accounts for 80% of perinatal morbidity and mortality in the United States. The cost of caring for premature infants who require long-term hospitalization can be as much as $500,000 per infant. Moreover, many of these babies suffer long-range medical problems as a result of their prematurity.
Currently there are several categories of tocolytic agent for the treatment of premature uterine contractions. These drugs include .beta.-sympathomimetics such as ritodrine and terbutaline, calcium channel antagonists and the prostaglandin synthase inhibitor indomethacin. The .beta.-sympathomimetic agents and calcium channel blockers have proven only partially successful in arresting uterine activity in women who are in latter stages of preterm labor. Moreover, these drugs produce maternal side-effects such as tachycardia, agitation, increased cardiac output, increased plasma volume, and even a small number of maternal fatalities. In women with contraindications to the use of .beta.-sympathomimetics, there are often no alternative therapies to offer for the treatment of preterm labor. In addition, these drugs have been associated with fetal tachycardia and other potentially harmful fetal side-effects, such as intracerebral hemorrhage. Calcium channel blockers such as nifedipine and magnesium sulfate have shown some efficacy, but also have shown untoward maternal and fetal side-effects, Vanden Veyuer, I. and Moisek.! "Prostaglandin Synthetase Inhibitors in Pregnancy," Obstetrical and Gynecological Survey, 1993; 48: 493-502; Eronen, M. et al., "The Effects of Indomethacin and a .beta.-Sympathomimetic Agent on the Fetal Ductus Arteriosus During Treatment of Premature Labor: A Randomized Double-Blind Study," Am. J. Obstet. Gynecol., 1991; 164: 141-146.
Indomethacin, an irreversible inhibitor of cyclooxygenase, and thus a prostaglandin synthesis inhibitor, has shown promise in the arrest of uterine contractions. However, indomethacin readily crosses the placental barrier, and causes undesirable side-effects in the fetus, including constriction of the ductus arteriosus and pulmonary hypertension, and altered cerebral blood flow. Gamissans, O. and Balasch, J. "Prostaglandin Synthetase Inhibitors in the Treatment of Preterm Birth," Preterm Birth: Causes, Prevention, and Management, 2d. ed., Fuchs, A. -R., Fuchs, F., and Stubblefield, P. G., eds., MacGraw-Hill, Inc., New York, 309-332.
Thus, while a few traditional pharmacologic agents exist for the treatment of premature labor in women, each has maternal and/or fetal side-effects which significantly limit their usefulness. The obstetrician is faced with the task of attempting to combat preterm uterine contractions with inadequate therapeutic tools.
Preterm premature rupture of the fetal membranes also referred to as "PROM" (that is, the bag of waters surrounding the fetus) and premature biochemical changes, such as premature dilatation and effacement also occur with preterm labor, and usually lead to premature expulsion of the fetus. These events are also mediated by prostaglandins, specifically PGE.sub.2. Rath, W. et al., "Biochemical Changes in Human Cervical Connective Tissue After Intracervical Application of Prostaglandin E.sub.2," Prostaglandins 1993; 45: 375-380. Currently, there is no pharmacologic treatment available for the treatment of premature cervical dilatation or PROM. Once the fetal membranes are ruptured, labor and delivery of the fetus are usually inevitable. However, if PROM occurs prior to 26-27 weeks gestation, the fetus is rarely able to survive. The only current treatment for premature dilatation and effacement is surgical ligation of the cervical canal. Yet the ligation itself often leads to uterine activity and preterm delivery.
Preeclampsia, a disease associated with an increased production of TXA.sub.2 and a shift in the ratio of PGI.sub.2 to TXA.sub.2, accounts for approximately 7% of all first pregnancies. Friedman, S. A., "Preeclampsia: A Review of the Role of Prostaglandins," Obstet. Gynecol., 1988; 71: 122-137. Zeeman, G. G. and Dekker, G. A., "Pathogenesis of Preeclampsia: A Hypothesis," Clin. Obstet. Gynecol., 1992; 35: 317-337. Preeclampsia is characterized by maternal hypertension, renal impairment including proteinuria, liver damage, systemic vasospasm, hypercoagulation and edema, and in severe cases, seizures and even death. Preeclampsia is the leading cause of maternal mortality in most developed nations. Preeclampsia also causes reduced uteroplacental blood flow and restricts the transfer of nutrients to the fetus. This leads to intrauterine growth retardation, fetal compromise, and often necessitates preterm delivery of the infant, which contributes to the high premature birth rate. Unfortunately, if the disease occurs during the late second or early third trimester, the fetus is too premature to survive outside the uterus. The mortality rate of these infants is extremely high.
There are very few treatments available for preeclampsia. Recently, low-dose aspirin has been used for the treatment of women who are at increased risk for developing preeclampsia. However, aspirin has not been effective at alleviating the disease symptoms once they occur. Thus, at present no palliative therapies exist for the treatment of this pregnancy complication.
Endometriosis, a condition in which the uterine lining proliferates and tissue escapes into the peritoneal cavity, is a painful and debilitating disorder which can require surgical correction and often threatens the reproductive ability of the patient. At present, hormonal therapy is used to inhibit uterine endometrial proliferation. In more severe cases, excess tissue is removed surgically. However, neither of these treatments relieve the painful effects of excess prostaglandin production by the endometrial tissues.
Rheumatoid arthritis is a chronic inflammatory disease localized to joint surfaces and characterized by synovial fibroblast proliferation, degradation of bone extracellular matrix, joint swelling and crippling pain. Lefer, A. M., "Eicosanoids as Mediators of Ischemia and Shock," Fed. Proc., 1985; 44: 275-280. PGE.sub.2 has been shown to stimulate the production of collagenase by isolated synoviocytes and elicits bone matrix degradation by osteoclasts. Synovial cells isolated from rheumatoid arthritis patients produce approximately ten times more PGE.sub.2 than cells from normal patients. Current therapies to treat rheumatoid arthritis rely on NSAIDS such as aspirin, ibuprofin and indomethacin and local administration of glucocorticoids such as dexamethasone and hydrocortisone to reduce joint pain and swelling. However, these agents cause several side-effects, chiefly gastric upset. Long-term glucocorticoid use causes liver and cardiovascular damage and loss of bone mass.
Adult respiratory distress syndrome (ARDS) and shock is a rare, but life threatening condition which can be precipitated by severe systemic infection, traumatic injury or shock and is characterized by acute endothelial cell damage in the lung, and in severe cases respiratory collapse and death. Proinflammatory cytokines, for example, interleukin-1, and tumor necrosis factor-.alpha., (TNF-.alpha.) are thought to be the primary mediators of ARDS and they are proposed to act via arachidonic acid metabolites and platelet-activating factor. PGI.sub.2 and PGE.sub.2 cause increased vascular permeability and interstitial edema within the lung parenchyma and accumulation of extravasated fluid and proteins in the alveolar space, while PGF.sub.2.alpha. and thromboxane cause vasoconstriction and pulmonary hypertension. PGE.sub.2 is also a modulator of neutrophil and monocyte chemotaxis to the lung. In addition, these patients often develop systemic hypotension, leading to compromise of multiple organ systems. Thromboxane also leads to platelet activation and adhesion to microvascular wall, precipitating thrombosis and ischemia. Animal models of ARDS have provided evidence that cyclooxygenase inhibitors may attenuate some of the clinical manifestations of ARDS. However, since the production of prostaglandins in this disease is progressive, it is clinically difficult to use conventional anti-cyclooxygenase agents for the effective treatment of ARDS.
Glomerulonephritis is an inflammatory disease of the kidney which results in the influx of inflammatory cells, such as neutrophils and monocytes into the renal parenchyma. Macrophages which migrate to the kidney from distal sites, release a myriad of cytokines and eicosanoids, for example, TxA.sub.2, leukotriene B.sub.4 resulting in reduced renal blood flow. Since TxA.sub.2 released by inflammatory macrophages is very deleterious to normal renal function, chronic injury may occur, ultimately leading to complete renal failure. In such cases, the patient is faced with certain long-term renal dialysis and even kidney transplantation. Traditional anti-inflammatory drugs such as non-specific anti-inflammatory drugs and glucocorticoids are usually not suitable since they cause generalized inhibition of prostaglandin biosynthesis, including inhibition of PGE.sub.2 which is required for normal renal physiologic function. Lianos, E. A., "Eicosanoid Biosynthesis and Role in Renal Immune Injury," Prostaglandins Leukot. Essent. Fatty Acids, 1990; 41:1-12.
It would be desirable to have drugs for the premature labor, PROM, premature effacement and dilation, endometriosis, rheumatoid arthritis, ARDS and glomerulitis, that would eliminate the condition, without the side effects of conventional treatments.